Antivirals currently on the market use small molecules as the active pharmaceutical ingredient and tend to be specific to certain (types of) viruses. However, through the incorporation of random mutations etc., viruses can easily evade the effects of antivirals targeting viral proteins, or parts of proteins.
MicroRNAs (miRNAs) are small RNAs (22 nt) that regulate eukaryotic gene expression by binding to specific messenger RNA transcripts, causing the mRNAs to be degraded or causing their translation to be repressed (Bartel 2004). MicroRNAs are encoded in the genomes of animals, plants and viruses; these genes are transcribed by RNA polymerase II as part of larger fold-back transcripts (primary miRNAs), which are processed in the nucleus by Drosha family members to form short stem-loops (pre-miRNAs), and then exported to the cytoplasm for processing by a Dicer family member to form the mature miRNA. It is estimated that miRNAs comprise 1% of genes in animals and may target up to 30% of genes in humans (Lewis, Burge et al. 2005). A given microRNA can potentially target hundreds of genes and by modulating a whole network of gene targets, can exert dramatic effects on various cellular processes (Giraldez, Mishima et al. 2006). The mechanism of microRNA function (generally down-regulation of host proteins) is distinct, but perhaps complementary, to other regulatory molecules (e.g. transcription factors). MicroRNAs have been shown to play key roles in cellular proliferation, differentiation, development and neuronal function; specific miRNAs also play a role in cancer formation, cardiovascular and metabolic diseases, and, more recently, viral infection.
MicroRNAs are an important component of viral-host interactions and have been shown to influence the outcome of viral infections, reviewed in (Ghosh, Mallick et al. 2008; Gottwein and Cullen 2008; Kumar 2008). Recent studies have demonstrated that specific host microRNAs are up-or down regulated upon infection with a particular virus and that some of these host microRNAs have target sites against specific viruses. This has led to the suggestion that microRNAs could mediate anti-viral defense; for example, mir-32 was shown to limit the replication of primate foamy virus (PFV) in human cells by targeting regions in the PFV genome (Lecellier, Dunoyer et al. 2005). In another study, mir-24 and mir-93 were shown to target vesicular stomatitis virus, leading to decreased replication of the virus in mice (Otsuka, Jing et al. 2007). However, rather than being “anti-viral”, the host microRNAs that target viruses may in fact be exploited by the viruses for persistence. From an evolutionary point of view, if the host miRNA target sites were disadvantageous to the virus, the virus could readily evolve to eliminate these sites (requiring only a single mutation) (Mahaj an, Drake et al. 2008). For example, it was shown that host microRNAs (mir-28, mir-125b, mir-150, mir-223 and mir-382) down regulate HIV mRNA and may be used by the virus to avoid being eliminated by the immune system (Huang, Wang et al. 2007). Furthermore, it is known that the host microRNA—mir-122, can actually be exploited by the virus to upregulate viral genes (by unknown mechanisms) (Jopling, Norman et al. 2006). The work listed above demonstrates that human or mouse microRNAs can play a pro- or anti-viral function by interacting with viral sequences; however, antiviral therapies based on microRNAs that specifically interact with viral genomes possess a number of disadvantages: 1) the viruses can mutate/evolve to escape the microRNA-target interactions 2) the identified microRNAs would be limited to function against the virus with the target site, rather than holding broad anti-viral potential.
More recently, it has been shown that cellular microRNAs that are induced or down regulated upon viral infection can also modulate host genes, which are co-factors for viral infection. For example, the miRNA cluster mir-17/92 was shown to be decreased upon HIV-1 infection and was shown with knockdown experiments to effect HIV-1 replication; this microRNA targets histone acetylase protein PCAF, which is a co-factor for the viral Tat protein (Triboulet, Mari et al. 2007).